Project Summary/Abstract Increasingly, medicinal chemists are moving away from ?flat? sp2-rich molecules for exploring bioactivity in recognition that the most selective compounds often contain a high degree of sp3 stereogenicity, therefore lending them three-dimensionality to match their biological targets. Additionally, stereochemically well-defined drugs frequently have fewer off-target effects owing to their high affinities for their intended targets, which can ultimately have a positive impact on human health. Therefore, synthetic methods that allow for the rapid construction of sp3-rich structures are of significant value to the drug discovery and manufacturing process. Recently, the use of strained organic intermediates to assemble stereochemically-dense products has garnered much attention. Highly strained reactive organic intermediates such as benzynes and other arynes, which were once thought to be purely theoretical, are now routinely used in conventional synthesis owing to their many uses, yet reactions with these intermediates generally give rise to planar products. However, a much less utilized strained intermediate is the strained cyclic allene (SCA) which has great potential in the construction of sp3-rich compounds. The proposed research aims to develop methodology that will allow 6-membered cyclic allenes, generated under mild conditions, to engage in highly regio- and stereoselective Diels-Alder cycloadditions with 2-pyrones and related 2-pyridones. The resulting products will be highly-functionalized, sp3-rich (hetero)cyclic structures that should prove as useful synthetic building blocks for the construction of complex molecules. Toward this goal, this methodology will be employed as the key step in a total synthesis of the indole alkaloid Alstilobanine A. This effort will result in the first asymmetric synthesis of this target and also the first use of SCAs in the total synthesis of a natural product.